Pro-pharma bias in the NICE menopause guidelines
Last week’s headlines about NICE’s (National Institute of Clinical Excellence) new menopause guidelines (click here) will have pleased the hormone replacement therapy (HRT) manufacturers.
“One million women could benefit from HRT, says NHS menopause guidance” The Guardian
“Women SHOULD be given HRT to fight menopause, says health watchdog because the benefits far outweigh the risks” Daily Mail.
This is a big change from the long-standing Medicines and Healthcare Devices Regulation Authority (MHRA) advice:
“to use HRT only for symptoms and in the lowest dose and for the shortest time possible.”
That cautious advice had been based on two Cochrane reviews, the latest versions of which had concluded:
“combined HRT significantly increased the risk of a coronary event (after one year’s use: Attributable risk 4 per 1000, 95% CI 3 to 7), venous thrombo-embolism (after one year’s use: AR 7 per 1000, 95% CI 4 to 11), stroke (after three years’ use: AR 18 per 1000, 95% CI 14 to 23), breast cancer (after 5.6 years’ use: AR 23 per 1000, 95% CI 19 to 29), gallbladder disease (after 5.6 years’ use: AR 27 per 1000, 95% CI 21 to 34) and death from lung cancer (after 5.6 years’ use plus 2.4 years’ additional follow-up: AR 9 per 1000, 95% CI 6 to 13).” Click here for the full review.
“there is strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events.” Click here for full review.
There hasn’t been any significant new research since either review was written, and NICE couldn’t avoid concluding that combined HRT increased venous thromboembolism and stroke. But by conducting a new review and restricting their main analysis to women under 60, which ruled out most Women’s Health Initiative (WHI) trial participants, NICE managed to conclude that there was no increased risk of cardiovascular disease or breast cancer. The point estimate remained that for every 1000 women taking combined HRT there would be an additional five heart attacks and five breast cancers, but with fewer trial events, NICE was able to claim that the differences could have occurred by chance. Casting doubt on the evidence that HRT increases cardiovascular disease and breast cancer made it easy to spin the conclusion that it was under-prescribed.
But surely NICE would not have commissioned doctors who were biased in favour of HRT? The conflicts of interest are listed in appendix C (click here). Here are the pecuniary ones.
Terry Aspray consultant physician, member of advisory board for Lilly Pharmaceuticals.
Deborah Holloway nurse, chair RCN women’s health conference sponsored by Bayer.
Sally Hope general practitioner, lecture fee from Consilient Health.
Nick Panay gynaecologist, advisory board and sponsored conference fees from Pfizer, sessions sponsored by Bayer and Novo-Nordisk and advisory board meeting coordinated by Shinogi pharmaceuticals.
Anthony Parsons gynaecologist, International Menopause Society meeting attendance fee paid by Novo Nordisk, and advisory board fee from Novo Nordisk.
None withdrew from discussion of the HRT advice section.
Dr Panay also forgot to mention his consultancies with Bayer and Abbott (click here) or his other fees from Baxter, Schering, Eli Lilly, Galen, Janssen Cilag, Merck, Novo Nordisk, Novogen, Organon, Orion, Procter & Gamble, Se-cure, Servier, Shire, Solvay, Storz, and Wyeth (click here).
The report’s chair Professor Mary Anne Lumsden and the expert advisor Professor Peter Collins declared no pecuniary interests, but were also forgetful.
I’m happy to forgive Professor Lumsden forgetting her 2004 HRT research supported by grants from NovoNordisk and Solvay pharmaceuticals (click here); after all it was along time ago.
But it’s disappointing that Peter Collins so conveniently forgot his more recent service as paid consultant to Eli Lilly, Berlex, Merck, Pantarhei, and Pfizer, and his lecture fees from Berlex, Merck, Pfizer, Novo Nordisk, and Organon (click here). Was he really the best person to interpret HRT’s cardiac risks?
I don’t think I’m being overly cynical in seeing bias here? In 2000, and 2004 Elena Hemminki and Klim McPherson wrote two important papers in which they extracted data from a large number of HRT trials in younger women, and showed, long before the WHI trials, that evidence of cardiovascular harm was being withheld by pharma. Neither paper was in an obscure or difficult to access journal.
Hemminki E, McPherson K. Value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease. Lancet. 2000 Feb 12;355(9203):566-9. (Click here)
McPherson K, Hemminki E. Synthesising licensing data to assess drug safety. BMJ. 2004 Feb 28;328(7438):518-20. (Click here)
Failing to cite these two papers is a pretty good test of a biased HRT review. The 253 page NICE guidelines with their five huge appendices had plenty of space to do so, but failed the test.
NICE should be ashamed of itself. Pharma must be pleased with their investment.
Doing it in 140 characters
The PICO method of summarising randomised controlled trials – Population studied, Intervention and Control group treatments, and primary Outcome – is good, but we often need to know more. Has the question already been answered, has it been judged important by patients and stakeholders, and is the trial large enough to have a reasonable chance of answering it reliably? Some protocols take many pages to tell us all that, some a side of A4, and a few fit it in to a 500 word abstract. Can anyone do it in 140 characters? Here’s two attempts.
PITCHES trial. Protocol here PITCHES CTIMP protocol V2 2 19_07_15 (4)
Here’s the tweet
JLA5preterm, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000493.pub2/full P f obs cholest, I300UDCA, C300placebo, O perinat death morbid, α.05, β.2, ER.05, RR.5
Total 129 characters because twitter contracts the hyperlink to 23; Seventeen to spare. The trial was funded before the James Lind Alliance completed its top ten list of research priorities for preterm labour, so the question has not actually been ranked. My made-up ranking of 5th in the preterm labour JLA list took 11 characters. The evidence is summarised in the hyperlinked Cochrane review. The population is [pregnant] females with obstetric cholestasis, the intervention group get a drug called ursodeoxycholic acid, and the control group placebo. There will be 300 women in each group. The primary outcome is a composite of baby death in the perinatal period or morbidity [severity undefined]. Assuming that we are willing to accept a 5% chance of getting a positive result when really there is no difference (alpha = 0.05) the trial has 80% power (beta = 0.2) of showing a difference, if the rate of death or morbidity is 5% (event rate 0.05) and the treatment (UDCA) really halves the risk of death or morbidity by 50% (a relative risk of 0.5). Cool eh?
35-39 trial. Protocol here
Here’s the tweet
JLA9stillbirth, http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.12328/abstract P preg f>35yrs, I315 IOL39w, C315 wait T+7-14, O Caesar, α.05, β.2, ER.3, RR.68
Hyperlink contracted to 23 again, making total 119, with 21 to spare. Again the 35-39 trial was funded before the James Lind Alliance completed its top ten list of research priorities for stillbirth prevention, so the 14 characters of “JLA9stillbirth” describe a fictional ranking. The hyperlink is to the relevant Cochrane review. The population is pregnant women aged over 35, the intervention group are offered labour induction at 39 weeks and the control group to wait until the usual time of term plus 7-14 days. 315 participants will be recruited to each group. The primary outcome is Caesarean section. With a 5% chance of getting a positive result when really there is no difference (alpha = 0.05) the trial has 80% power (beta = 0.2) of showing a difference, if the control Caesarean event rate (ER) is 30% (event rate 0.3) and induction really reduces this by one third (a relative risk of 0.67).
My suggested hashtag #RCTinatweet is only 12 characters so could be added to both. I really need to get out more!
By Robert Frost
There are two reasons to disbelieve the argument from design for a divine creator; Darwinian natural selection is a more parsimonious explanation, and this sonnet. A mutant white spider has killed a mutant white moth on a mutant white flower. If that was by design … .
I found a dimpled spider, fat and white,
On a white heal-all, holding up a moth
Like a white piece of rigid satin cloth —
Assorted characters of death and blight
Mixed ready to begin the morning right,
Like the ingredients of a witches’ broth —
A snow-drop spider, a flower like a froth,
And dead wings carried like a paper kite.
What had that flower to do with being white,
The wayside blue and innocent heal-all?
What brought the kindred spider to that height,
Then steered the white moth thither in the night?
What but design of darkness to appall?–
If design govern in a thing so small.
Rubbing out the truth
Dan Pagis was a child survivor of the Holocaust; his poem Written in Pencil in the Sealed Railway Car is inscribed in stone at the Belzec death camp victims memorial.
|here in this carload
i am eve
with abel my son
if you see my other son
cain son of man
tell him that i
Homily is a less famous Holocaust poem. Its three short paragraphs don’t pretend to solve the problem of pain. But they remind us that suffering is not the worst that can happen; it’s even worse to have the truth of our suffering – perhaps only scratched in pencil – rubbed out.
From the start the forces were unequal: Satan a grand seigneur in heaven, Job mere flesh and blood. And anyway the contest was unfair. Job, who had lost all his wealth and been bereaved of his sons and daughters, and stricken with loathsome boils, wasn’t even aware that it was a contest.
Because he complained too much the referee silenced him. So, having accepted this decision in silence, he defeated his opponent without even realising it. Therefore his wealth was restored, he was given sons and daughters – new ones of course – and his grief for the first children was taken away.
We might imagine that this retribution was the most terrible thing of all. We might imagine that the most terrible thing was Job’s ignorance: not understanding whom he had defeated or even that he had won. But in fact the most terrible thing of all is that Job never existed and is just a parable.
Two Camino de Santiago poems
Discussing the best way to die, we decided that suddenly without warning but not right now, would suit most of us. So we read Roger McGough over our pilgrim’s dinner.
Let Me Die a Youngman’s Death
Let me die a youngman’s death
not a clean and inbetween
the sheets holywater death
not a famous-last-words
peaceful out of breath death
When I’m 73
and in constant good tumour
may I be mown down at dawn
by a bright red sports car
on my way home
from an allnight party
Or when I’m 91
with silver hair
and sitting in a barber’s chair
may rival gangsters
with hamfisted tommyguns burst in
and give me a short back and insides
Or when I’m 104
and banned from the Cavern
may my mistress
catching me in bed with her daughter
and fearing for her son
cut me up into little pieces
and throw away every piece but one
Let me die a youngman’s death
not a free from sin tiptoe in
candle wax and waning death
not a curtains drawn by angels borne
‘what a nice way to go’ death
By Roger McGough
The details, “banned from the Cavern”,”fearing for her daughter”, “every piece but one”, worked for me, but one pilgrim didn’t like it at all – upsetting, not funny, not good.
So I tried to make amends with a different take on old age, Jenny Joseph’s When I am old I shall wear purple. Official title Warning.
When I am an old woman I shall wear purple
With a red hat which doesn’t go, and doesn’t suit me.
And I shall spend my pension on brandy and summer gloves
And satin sandals, and say we’ve no money for butter.
I shall sit down on the pavement when I’m tired
And gobble up samples in shops and press alarm bells
And run my stick along the public railings
And make up for the sobriety of my youth.
I shall go out in my slippers in the rain
And pick flowers in other people’s gardens
And learn to spit.
You can wear terrible shirts and grow more fat
And eat three pounds of sausages at a go
Or only bread and pickle for a week
And hoard pens and pencils and beermats and things in boxes.
But now we must have clothes that keep us dry
And pay our rent and not swear in the street
And set a good example for the children.
We must have friends to dinner and read the papers.
But maybe I ought to practice a little now?
So people who know me are not too shocked and surprised
When suddenly I am old, and start to wear purple.
By Jenny Joseph
The final verse is the killer; it really is about old age. My pilgrim friend was right, a much better poem.
By CK Williams
Published in 2005, On the Metro is one of CK Williams’ later poems. The subject is risky – an old man admiring a younger girl – but look at the care he takes, with each long line, to make his meaning clear. I think he succeeded. He died on Sept 20th.
On the metro, I have to ask a young woman to move the packages
……..beside her to make room for me;
she’s reading, her foot propped on the seat in front of her, and barely
……..looks up as she pulls them to her.
I sit, take out my own book—Cioran, The Temptation to Exist—and
……..notice her glancing up from hers
to take in the title of mine, and then, as Gombrowicz puts it, she
……..“affirms herself physically,” that is,
becomes present in a way she hadn’t been before: though she hasn’t
……..moved, she’s allowed herself
to come more sharply into focus, be more accessible to my sensual
……..perception, so I can’t help but remark
her strong figure and very tan skin—(how literally golden young
……..women can look at the end of summer.)
She leans back now, and as the train rocks and her arm brushes mine
……..she doesn’t pull it away;
she seems to be allowing our surfaces to unite: the fine hairs on both
……..our forearms, sensitive, alive,
achingly alive, bring news of someone touched, someone sensed, and
……..thus acknowledged, known.
I understand that in no way is she offering more than this, and in truth
……..I have no desire for more,
but it’s still enough for me to be taken by a surge, first of warmth then
……..of something like its opposite:
a memory—a girl I’d mooned for from afar, across the table from me
……..in the library in school now,
our feet I thought touching, touching even again, and then, with all I
……..craved that touch to mean,
my having to realize it wasn’t her flesh my flesh for that gleaming time
……..had pressed, but a table leg.
The young woman today removes her arm now, stands, swaying
……..against the lurch of the slowing train,
and crossing before me brushes my knee and does that thing again,
……..asserts her bodily being again,
(Gombrowicz again), then quickly moves to the door of the car and
……..descends, not once looking back,
(to my relief not looking back), and I allow myself the thought that
……..though I must be to her again
as senseless as that table of my youth, as wooden, as unfeeling, perhaps
……..there was a moment I was not.
Another wrong (about randomisation) educationalist
Jo Boaler, author, Stanford professor (click here), and founder of the educational website YouCubed (click here) is visiting the UK to persuade schools to take up her maths teaching ideas (click here). She objects to rote learning of times tables. According to the Times Education Supplement (click here) she has said:
“Governments saying everybody has to memorise their times tables to 12 times 12 is absolutely disastrous.”
Blimey! But she has her reasons. She believes forcing weak children to learn tables makes them anxious about maths in general.
“What we know now is that when you give things to kids like a timed multiplication test, about a third of them develop anxiety. For those kids the working memory which holds maths facts is blocked and they can’t access it.”
“Some kids aren’t fast memorisers,and they decide from an early age that they can’t do maths because of the timed maths tests.”
Even bright kids are harmed:
“Other kids may be OK but see maths as a shallow subject which is about recall of facts and disengage. So [tables cause] huge damage”.
It all sounds plausible, her webpages cite whole libraries of academic papers, and she is obviously a charismatic educationalist. Judging by her twitter feed @joboaler many teachers adore her.
But others argue that learning tables is a vital early step in getting comfortable with mathematics. Click here for one. They also have theories and academic papers in support.
The research cited by each side is impenetrable to anyone uncommitted to the argument the author is advocating, and I’m certainly not qualified to judge it.
But I am qualified to say that in an area like maths teaching where factors like innate ability, teacher enthusiasm and parental engagement almost certainly influence results, the only reliable way to judge who is right, is a randomised controlled trial. But Jo Boaler cites none, and Google can’t find any.
I am also qualified to state that Jo Boaler doesn’t understand the limitations of observational data and the need for randomised trials in education. In a paper (click here) critiquing a US National Mathematics Advisory Panel that had advocated teaching tables in 2008, she wrote,:
“When comparing teaching approaches to consider which is more effective, random or equal assignment may be thought of as presenting a research ideal. If students are assigned to random or equal groups and given different treatments, and one treatment results in better outcomes, then researchers have a strong case for making causal statements. Experiments such as these have emanated from medical research, and they lend themselves to the controlled conditions of laboratories. However, when researching learning in complicated places such as schools, such models become highly impractical and, some would say, implausible.”
“Researchers in mathematics education do not need to assign students to groups in quasi-experimental studies, taking control of their education, as they can employ statistical methods to control for differences in student characteristics. Using logistic regression analysis, for example, researchers can control for factors such as prior mathematics achievement, gender, and socioeconomic status. It could be argued that researchers cannot control for every variable that may affect a student in a population, but they can control for all those known to be reasonable […]”
That’s wrong Jo Boaler. Other educationalists have expressed similar sentiments, and they are wrong too. Not just a bit wrong, but absolutely 100% wrong. The exact opposite of correct. Score gamma triple minus in the “education intervention evaluation exam”. Go to the back of the class Jo Boaler.
It is the very complexity of education, the many unknown factors that influence outcomes, that justifies randomisation. “Prior mathematics achievement, gender, and socioeconomic status” aren’t the problem. Jo Boaler is right about that; we can measure them and, at least in principle, control for them using logistic regression analysis. But, by definition, no amount of fancy statistics can ever control for unknown factors; they are unknown factors. The only way to have any assurance that they are more or less equal between the two groups under study is to allocate the students at random.
This misunderstanding about randomisation causes trouble in two ways. If Jo Boaler is wrong, her ideas are condemning thousands, maybe millions, of children to not learn their tables, and a lifetime of innumeracy.
But what if she is right? In that case her failure to test her ideas against well-conducted randomised trials allows governments all over the world to continue forcing children to learn their tables by rote and condemn even more to a lifetime of fear of mathematics.
What a pity no-one taught Jo Boaler how to evaluate educational interventions properly.